NM_198578.4:c.4624C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198578.4(LRRK2):c.4624C>T(p.Pro1542Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0315 in 1,612,210 control chromosomes in the GnomAD database, including 1,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1542P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.030 ( 145 hom., cov: 32)

Exomes 𝑓: 0.032 ( 1065 hom. )

Consequence

LRRK2
NM_198578.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 5.49

Publications

33 publications found

Variant links:

Genes affected

LRRK2 (HGNC:18618): (leucine rich repeat kinase 2) This gene is a member of the leucine-rich repeat kinase family and encodes a protein with an ankryin repeat region, a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, a MLK-like domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Mutations in this gene have been associated with Parkinson disease-8. [provided by RefSeq, Jul 2008]

LRRK2 Gene-Disease associations (from GenCC):

autosomal dominant Parkinson disease 8
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
Parkinson disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hereditary late onset Parkinson disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LRRK2 links:

ENSG00000258167 (HGNC:):

ENSG00000258167 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028391778).

BP6

Variant 12-40314059-C-T is Benign according to our data. Variant chr12-40314059-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 39193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0296 (4497/151954) while in subpopulation NFE AF = 0.035 (2380/67924). AF 95% confidence interval is 0.0339. There are 145 homozygotes in GnomAd4. There are 2447 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4497 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRK2	NM_198578.4 link	c.4624C>T	p.Pro1542Ser	missense_variant	Exon 32 of 51	ENST00000298910.12	NP_940980.4	Q5S007Q17RV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRK2	ENST00000298910.12 link	c.4624C>T	p.Pro1542Ser	missense_variant	Exon 32 of 51	1	NM_198578.4	ENSP00000298910.7		Q5S007

Frequencies

GnomAD3 genomes

AF:

0.0296

AC:

4497

AN:

151836

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00532

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0192

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00726

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0350

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0318

AC:

7966

AN:

250762

AF XY:

0.0318

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.0235

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.0324

Gnomad OTH exome

AF:

0.0306

GnomAD4 exome

AF:

0.0317

AC:

46326

AN:

1460256

Hom.:

1065

Cov.:

AF XY:

0.0314

AC XY:

22843

AN XY:

726462

show subpopulations

African (AFR)

AF:

0.00356

AC:

119

AN:

33404

American (AMR)

AF:

0.0226

AC:

1007

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

464

AN:

26074

East Asian (EAS)

AF:

0.000151

AC:

AN:

39646

South Asian (SAS)

AF:

0.00942

AC:

812

AN:

86222

European-Finnish (FIN)

AF:

0.120

AC:

6377

AN:

53356

Middle Eastern (MID)

AF:

0.00903

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0322

AC:

35719

AN:

1110862

Other (OTH)

AF:

0.0294

AC:

1770

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

2180

4360

6540

8720

10900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1310

2620

3930

5240

6550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0296

AC:

4497

AN:

151954

Hom.:

145

Cov.:

AF XY:

0.0329

AC XY:

2447

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00531

AC:

220

AN:

41464

American (AMR)

AF:

0.0192

AC:

292

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00727

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.138

AC:

1453

AN:

10552

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0350

AC:

2380

AN:

67924

Other (OTH)

AF:

0.0175

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

202

403

605

806

1008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0267

Hom.:

127

Bravo

AF:

0.0188

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0329

AC:

283

ExAC

AF:

0.0300

AC:

3645

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0298

EpiControl

AF:

0.0264

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant Parkinson disease 8

Benign:3Other:1

Sep 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Sep 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32677286, 26503572) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 17, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.6

PhyloP100

5.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Benign

0.16

Sift4G

Uncertain

0.0060

Polyphen

0.98

Vest4

0.49

MPC

0.42

ClinPred

0.028

GERP RS

5.8

Varity_R

0.11

gMVP

0.78

Mutation Taster

=79/21

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over